Proband-Only Clinical Exome Sequencing for Neurodevelopmental Disabilities

Area of Science:

• Genetics
• Clinical Diagnostics
• Neurodevelopmental Disorders

Background:

• Whole exome sequencing (WES) in family trios has high diagnostic yield but is costly.
• Proband-only clinical exome sequencing (CES) is explored as a cost-effective alternative.
• Focus on patients with neurodevelopmental disabilities (NDDs).

Purpose of the Study:

• To evaluate the diagnostic yield of proband-only CES in NDD patients.
• To assess the utility of proband-only CES as a standalone diagnostic tool.
• To determine if proband-only CES is a practical clinical approach.

Main Methods:

• Observational, retrospective study of 108 unrelated NDD patients.
• Proband-only clinical exome sequencing performed, targeting 4503 disease-causing genes.
• Follow-up parental testing conducted for variant reclassification.

Main Results:

• Overall diagnostic rate of 38.0% (41/108) with proband-only CES.
• An additional 3.7% diagnostic yield (4/108) achieved via parental testing.
• Final diagnostic rate reached 41.7% (45/108), identifying various genetic variants and copy number variations.

Conclusions:

• Proband-only CES is a practical and effective diagnostic tool for NDDs.
• A cost-effective strategy involves proband-only CES followed by targeted parental testing.
• Implementation in clinical settings for NDD diagnosis is recommended.